Physostigmines, also called eserines, are known cholinesterase inhibitors. These compounds are also useful in the treatment of glaucoma, Myasthenia Gravis, and Alzheimer's disease, and as antidotes against poisoning with organophosphates.
It has been discovered that the natural isomer of physostigmine has blocking properties as well as agonist properties at the neuromuscular AChR. By contrast, (+)-physostigmine shows only negligible inhibition of cholineste:rase (ChE). See Brossi et al., FEBS Lett., Vol. 201, pages 190-192 (1986).
Even though (+)-physostigmine has only negligible ChE inhibitory activity, it is effective as a protective pretreatment drug against multiple lethal doses of sarin, see Albuquerque et al, Fundam. Appl. Caltoxicol., Vol. 5, pages 182-203 (1985). The observed beneficial protection appears to be due to direct interactions of the carbamates with the postsynaptic nicotinic AChR. The protective effectiveness of the carbamates against organophosphates appears to be related to the direct ability of the carbamates to decrease the hyperactivation caused by accumulation of the neurotransmitter.
The above information, is important in evaluation of potential new pharmacological agents for treating cholinergic disorders, for example, Myasthenia Gravis and Alzheimer's disease. Potential agents can be evaluated for potency in vitro by testing the agents against electric eel and human red blood cell acetylcholinesterase (AChE) and human plasma butyrylcholinesterase, (BChE).
Since defects in the cholinergic system have been suggested to underlie cognitive impairments associated with normal aging and Alzheimer's disease (Bartus et al., Science 217:408-417 (1982); Fischer et al., Neurobiol. Aging 13:9-23 (1992)), much research has focused on the development of cholinomimetic replacement therapy as a potential treatment of these impairments. Among them, cholinesterase inhibitors, such as physostigmine (Phy) and tetrahydroaminoacridine (THA), have been investigated for memory-enhancing effects in both animals (Rupniak et al., Neurobiol. Aging 11:09-613 (1990); Murray et al. Psychopharmacology 105:134-136 (1991)) and human patients (Mohs et al., J. A. Geriatr. Soc. 33:749-757 (1985); Summers et al., N. Engl. J. Med. 315:1241-1245 (1986)).
Unfortunately, however, the therapeutic usefulness of Physostigmine is limited by its short duration of action, narrow therapeutic window and peripheral cholinergic effects (Pomponi et al., Aging 2:125-153 (1990)). Although oral administration of THA is convenient for clinical use, dose-related hepatotoxicity limits its clinical value (Marx, Science 238:1041-1042 (1987)) and lower, safer doses of THA seem less effective than higher hepatotoxic doses (Gauthier et al., N. Engl. J. Med. 322:1272-1276 (1990).
Further, another cholinesterase inhibitor, heptyl-physostigmine (heptyl-Phy), a carbamate derivative of Physostigmine, has also been considered as a candidate for cholinomimetic therapy of cognitive impairments (Brufani et al., Pharmacol. Biochem. Behav. 26:625-629 (1987); Dawson et al., Pharmacol. Blochem. Behav. 39:865-871 (1991); De Sarno et al., Neurochem. Res. 14:971-977, (1989)). This compound appears to have greater lipophilicity, longer inhibitory action on cholinesterase and more persistent increases in acetylcholine in brain with less toxicity than the parent compound (Brufani et al., Pharmacol. Biochem. Behav. 26:625-629 (1987)).
It is also reported that heptyl-Phy facilitates memory consolidation in mice in a passive avoidance test (Brufani et al., Pharmacol. Biochem. Behav. 26:625-629 (1987)), and reverses the performance deficits induced by scopolamine in a range of rodent behavioral tests of long-term and working memory (Dawson et al., Pharmacol Biochem Behav 39:865-871 (1991)). In a recent study, heptyl-Phy attenuated the scopolamine-induced learning impairment of rats in a 14-unit T-maze (Iijima et al., Neurosci Lett (in press 1992)). However, the therapeutic window of heptyl-Phy did not seem wide enough for clinical use.
There is a major problem in this art area regarding acceptable therapeutic windows for highly selective agents active in vivo. In a clinical setting there are variations between patients with regard to handling cholinomimetic agents (i.e., individual differences in absorption, metabolism and excretion, as well as cholinergic dysfunction due to the disease process), which have a strong impact on the efficacy of the drug, and in particular with classes of drugs used in the elderly, the portion of the population that Alzheimer's disease predominantly inflicts.
Such problems present major complications for agents that have a relatively narrow therapeutic window, as optimal dosing is then difficult to achieve. This is particularly true in the elderly, where individual differences in drug handling can be quite large, and affected by the concomitant administration of other drugs for the management of other diseases in the patient. Since many patients needing cholinomimetic therapy are elderly and have other diseases, the problem in this art area is particularly acute.
Accordingly, there is need in the art for highly selective agents active in vivo, having an acceptable therapeutic window, and minimal side effects, for cholinomimetic replacement therapy and treatment of these impairments, which agents have memory-enhancing effects in both animals and human patients.